Phase II study of tosedostat with cytarabine or decitabine in newly diagnosed older patients with acute myeloid leukaemia or high-risk MDS

Tosedostat, an oral aminopeptidase inhibitor, has synergy with cytarabine and hypomethylating agents. We performed a Phase II trial to determine rates of complete remission (CR) and survival using tosedostat with cytarabine or decitabine in older patients with untreated acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS). Thirty-four patients 60years old (median age 70years; range, 60-83) were randomized to receive tosedostat (120mg on days 1-21 or 180mg continuously) with 5d of either cytarabine (1g/m(2)/d) or decitabine (20mg/m(2)/d) every 35d. Twenty-nine patients (85%) had AML, including 15 (44%) with secondary AML/MDS, and 5 (15%) had MDS-refractory anaemia with excess blasts type 2. The CR/CR with incomplete count recovery (CRi) rate was 53% [9 in each arm; 14 CR (41%) and 4 CRi (12%)], attained in 6 of 14 patients with adverse cytogenetics and 4 of 7 with FLT3-internal tandem duplication mutations. Median follow-up was 112months (range, 05-223), and median survival was 115months (95% confidence interval, 52-167). Twenty-three patients (676%) were treated as outpatients and 10 of these patients required hospitalization for febrile neutropenia. No Grade 3-4 non-haematological toxicities required withdrawal from study. Tosedostat with cytarabine or decitabine is tolerated in older patients with untreated AML/MDS, results in a CR/CRi rate of >50%, and warrants further study in larger trials.